Project Summary Bone is a dynamic tissue which requires intricate regulatory processes that must work in synchrony to maintain a healthy skeleton. Alterations in this regulation can lead to bone disease. Diabetes is characterized by hyperglycemia resulting from a lack of insulin or reduced insulin sensitivity and affects over 20 million people in the United States. Individuals with diabetes experience decreased bone quality and an increased susceptibility to fracture, leading to significant disability and morbidity. Diabetic bone disease primarily results from an anabolic defect in which there is deficient osteoblast activity, in contrast to the mainly catabolic dysregulation seen in osteoporosis. Osteoblasts produce fibrillar collagens during bone formation, which require lysyl oxidase (LOX) enzyme-dependent modification of specific lysine residues and subsequent cross-linking in order to form a functional fibrillar network and confer strength to bone. The number of lysyl oxidase-dependent cross-links in collagen is decreased in diabetes, leading to compromised bone microarchitecture. Incretins are gastric hormones released by intestinal K-cells into the circulation which regulate insulin release from pancreatic beta cells. One of these hormones, glucose-dependent insulinotropic peptide or GIP is anabolic in bone partially mediated independent of its effects action on the pancreas to stimulate insulin release. Deletion of the receptor for this hormone, which is expressed on osteoblasts, results in a reduction in bone strength and material properties in mice similar to the low bone formation osteopenia seen in diabetes. GIP also augments LOX activity in osteoblasts, resulting in an increase in mature, stable collagen cross-links. In diabetes the cellular response to GIP is abnormally low, while serum GIP levels remain the same or elevated. Hypothesis: Diabetes interferes with GIP-stimulated LOX expression in osteoblasts. This is mediated by GIP receptor desensitization and leads to the osteopenic phenotype seen in mouse and human diabetic bone. Aim 1: Evaluate the bone phenotype of diabetic and non-diabetic LOX +/- and wild type bones and establish diminished LOX levels as a critical determinant of bone quality in diabetes Aim 2: Determine the mechanism of GIP up-regulation of LOX under normal conditions in osteoblasts and assess for molecular defects in GIPR signaling under diabetic conditions to develop approaches for treating diabetic osteopenia.